The production of red blood cells, or erythropoiesis, is regulated by the sensing of the oxygen carrying capacity of the blood by the kidney and the subsequent production and release of erythropoietin (EPO). In normal individuals, that production and release of EPO allows hemoglobin (Hb) concentrations to be maintained at normal levels. In many patient populations, however, the administration of exogenous EPO is required to maintain Hb concentrations above 10 g/dL. These patient populations are diverse and include patients with chronic renal disease, HIV-infection, and cancer.
EPO is a glycoprotein hormone that exerts its erythropoietic effect through the EPO receptor (EpoR) and, as such, there is a series of both extra and intracellular events that must occur for EPO to regulate red blood cell production. Along these lines, and central to the current discussion of erythropoietic agents such as EPO, it has been observed that certain patients respond normally to pharmacologic concentrations of EPO (good responders), while other patients do not respond to typical pharmacologic concentrations (poor responders). Patients that are poor responders to EPO may be at risk for increased morbidity and mortality (1). Indeed, it has been further observed that the inability of these patients to reach a target hemoglobin concentration, in combination with the increased epoetin-α dose that must typically be administered, places these patients at an increased risk of death, myocardial infarction, congestive heart failure, or stroke (2).
Many factors may cause a poor response to an erythropoietic agent, such as EPO, including inadequate doses of the agent, functional or absolute iron deficiency, blood loss, infection, inflammation, secondary hyperparathyroidism, aluminum toxicity, hemolysis, malignancies, hematologic disorders, AIDS, pregnancy, and vitamin deficiency (3). Cytokines (IL-1, IL-6, interferon-y, tumor necrosis factor), hepcidin, EpoR and the subsequent intracellular signaling have also been identified as potential regulators of EPO responsiveness (4, 5). Further, there is an interaction between IL-6 and hepcidin that is responsible for hypoferremia that may limit ESA response (6, 7), and soluble EpoR concentrations may be associated with EPO resistance in end stage renal disease (ESRD) (8, 9). To date, however, and despite the identification of factors that may cause different patients to respond differently to erythropoietic agents, biomarkers have yet to be identified that allow a patient's response to an erythropoietic agent to be effectively predicted.